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Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E-/- mice and rabbits fed a high-fat and -cholesterol diet.

AbstractBACKGROUND:
Glycosphingolipids, integral components of the cell membrane, have been shown to serve as messengers, transducing growth factor-initiated phenotypes. Here, we have examined whether inhibition of glycosphingolipid synthesis could ameliorate atherosclerosis and arterial stiffness in transgenic mice and rabbits.
METHODS AND RESULTS:
Apolipoprotein E(-/-) mice (12 weeks of age; n=6) were fed regular chow or a Western diet (1.25% cholesterol, 2% fat). Mice were fed 5 or 10 mg/kg of an inhibitor of glycosphingolipid synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), solubilized in vehicle (5% Tween-80 in PBS); the placebo group received vehicle only. At 20 and 36 weeks of age, serial echocardiography was performed to measure aortic intima-media thickening. Aortic pulse-wave velocity measured vascular stiffness. Feeding mice a Western diet markedly increased aortic pulse-wave velocity, intima-media thickening, oxidized low-density lipoprotein, Ca(2+) deposits, and glucosylceramide and lactosylceramide synthase activity. These were dose-dependently decreased by feeding D-PDMP. In liver, D-PDMP decreased cholesterol and triglyceride levels by raising the expression of SREBP2, low-density lipoprotein receptor, HMGCo-A reductase, and the cholesterol efflux genes (eg, ABCG5, ABCG8). D-PDMP affected very-low-density lipoprotein catabolism by increasing the gene expression for lipoprotein lipase and very-low-density lipoprotein receptor. Rabbits fed a Western diet for 90 days had extensive atherosclerosis accompanied by a 17.5-fold increase in total cholesterol levels and a 3-fold increase in lactosylceramide levels. This was completely prevented by feeding D-PDMP.
CONCLUSIONS:
Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E(-/-) mice and rabbits. Thus, inhibition of glycosphingolipid synthesis may be a novel approach to ameliorate atherosclerosis and arterial stiffness.
AuthorsSubroto Chatterjee, Djahida Bedja, Sumita Mishra, Christine Amuzie, Alberto Avolio, David A Kass, Dan Berkowitz, Mark Renehan
JournalCirculation (Circulation) Vol. 129 Issue 23 Pg. 2403-13 (Jun 10 2014) ISSN: 1524-4539 [Electronic] United States
PMID24710030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright© 2014 American Heart Association, Inc.
Chemical References
  • Antigens, CD
  • Apolipoproteins E
  • Cholesterol, Dietary
  • Enzyme Inhibitors
  • Glucosylceramides
  • Glycosphingolipids
  • Lactosylceramides
  • Lipoproteins, LDL
  • Morpholines
  • oxidized low density lipoprotein
  • CDw17 antigen
  • RV 538
  • Calcium
Topics
  • Animals
  • Antigens, CD (metabolism)
  • Aorta (diagnostic imaging, drug effects, metabolism)
  • Apolipoproteins E (genetics)
  • Calcium (metabolism)
  • Cholesterol, Dietary (pharmacology)
  • Coronary Artery Disease (drug therapy, genetics, metabolism)
  • Diet, High-Fat
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression Regulation (drug effects)
  • Glucosylceramides (metabolism)
  • Glycosphingolipids (biosynthesis, metabolism)
  • Hyperlipidemias (drug therapy, genetics, metabolism)
  • Lactosylceramides (metabolism)
  • Lipoproteins, LDL (metabolism)
  • Male
  • Mice
  • Mice, Knockout
  • Models, Cardiovascular
  • Morpholines (pharmacology)
  • Pulsatile Flow (drug effects)
  • Rabbits
  • Ultrasonography
  • Vascular Stiffness (drug effects)

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